4-PHENYL-4-PHENYLPROPYL(ENYL)-PIPERIDINES AS TACHYKININ ANTAGONISTS

Abstract: The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts and prodrugs thereof, wherein X represents a propylene or propenylene chain optionally substituted by one or more of R<4>, R<5>, R<6> and R<7>; m is 2, 3 or 4; n is 0, 1 or 2 when m is 2 or 3, and n is 0 or 1 when m is 4; R<1> represents optionally substituted phenyl; R<2> represents optionally substituted phenyl, heteroaryl, benzhydryl or benzyl; R<3> represents H, COR<9>, CO2R<10>, COCONR<10>R<11>, COCO2R<10>, SO2R<15>, CONR<10>SO2R<15>, C1-6alkyl optionally substituted by a group selected from (CO2R<10>, CONR<10>R<11>, hydroxy, cyano, COR<9>, NR<10>R<11>, C(NOH)NR<10>R<11>, CONHphenyl(C1-4alkyl), COCO2R<10>, COCONR<10>R<11>, SO2R<15>, CONR<10>SO2R<15> and optionally substituted phenyl), Y-R<8> or CO-Z-(CH2)q-R<12>; R<4> and R<5> each independently represent H, C1-6alkyl, C3-6cycloalkyl, C3-5cycloalkylmethyl, hydroxy or C1-6alkoxy, or R<4> and R<5> together form a group =0; R<6> and R<7> each independently represents H, C1-6alkyl, C3-6cycloalkyl, C3-5cycloalkylmethyl, hydroxy or C1-6alkoxy or R<6> and R<7> together form a group =0; R<8> represents an optionally substituted aromatic heterocycle; R<9> represents H, C1-6alkyl, C3-6cycloalkyl, C3-5cycloalkylmethyl, or phenyl; R<10> and R<11> each independently represent H, C1-6alkyl, C3-6cycloalkyl or C3-5cycloalkylmethyl; R<12> represents NR<13>R<14> or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; R<13> and R<14> each independently represent H, C1-6alkyl, C3-6cycloalkyl, C3-5cycloalkylmethyl, optionally substituted phenyl or phenylC1-4alkyl; R<15> represents C1-6alkyl, C3-6cycloalkyl, C3-5cycloalkylmethyl, trifluoromethyl or optionally substituted phenyl; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Z represents CH2, O, S or NR<10>; and q represents 0, 1, 2, 3, 4, 5 or 6. The compounds are tachykinin antagonists useful for treating pain or inflammation, migraine or emesis.

Description: 4-PHENYL-4-PHENYLPR0PYL(ENYL)-PIPERIDINES AS TACHYKININ ANTAGONISTS. This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azacyclic ring system substituted by an aryl moiety and an arylalkyl or arylalkenyl moiety. The tachykinins are a group of naturally- occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems. The tachykinins are distinguished by a conserved carboxy-terminal sequence: Phe-X-Gly-Leu-Met-NH 2 At present, there are three known mammalian tachykinins referred to as substance P, neurokinin A (NKA, substance , neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E. Maggio, Peptides (1985) 6 . (suppl. 3), 237-242). The current nomenclature designates the three tachykinin receptors mediating the biological actions of substance P, NKA and NKB as the NKi, NK 2 and NK 3 receptors, respectively. Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardivascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitus, inflammatory diseases of the gut including ulcerative colitis and Crohn disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper- reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) .13. / 23-93. Tachykinin antagonists may also be useful in the treatment of e esis [F.D. Tattersall et. al., Eur. Pharmacol., (1993) 250, R5-R6]. Tachykinin antagonists are also believed to be useful in allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 6 . 1361-7], im unoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9], and as anticonvulsants [Garant et al.. Brain Research (1986) 382 372-8]. Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al. , Cancer Research (1992) 52. 4554-7] . It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthy ic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus eryth atosis (European patent specification no. 0 436 334) , conjuctivitis, vernal conjunctivitis, contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent specification no. 0 394 989) . In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non- peptide tachykinin antagonists are sought. In essence, this invention provides a class of potent non-peptide tachykinin antagonists. The present invention provides a compound of formula (I) , or a pharmaceutically acceptable salt or prodrug thereof: « '-x N R * - (I) wherein X represents a propylene or propenylene chain optionally substituted by one or more of R 4 , R 5 , R 6 and R 7 ; is 2, 3 or 4; n is 0, 1 or 2 when is 2 or 3, and n is 0 or 1 when m is 4; - R 1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Cι_galkyl, C2- 6 alker_yl, C 2 - 6 alkynyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoro ethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a C0R , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b each independently represent H, Cι_ 6 alkyl, phenyl or trifluoromethyl; R 2 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C2- 6 alkenyl, C2-6alkynyl, C3_6cycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R , where R a and R are as previously defined; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each heteroaryl and each phenyl moiety of benzyl and benzhydryl may be substituted by Ci-galkyl, Cι_.galkoxy, halo or trifluoromethyl; R 3 represents H, COR 9 , C0 2 R 10 , COCONR 10 R 1:L , COC0 2 R 10 , S0 2 R 15 , CONR 10 SO 2 R 15 , Ci-ealkyl optionally substituted by a group selected from (CO2R 10 , CONR 10 R 11 , hydroxy, cyano, COR 9 , NR 10 R 1:L , C(NOH)NR 10 R 1:L , CONHphenyl(C 1 _ 4 alkyl) , COC0 2 R 10 , COCONR 10 R 1:L , S0 2 R 15 , CONR 10 Sθ2R 15 and phenyl optionally substituted by one or more substituents selected from Cι_galkyl, Ci-galkoxy, halo and trifluoromethyl), Y-R 8 or CO-Z-(CH 2 ) q -R 12 ; R 4 and R 5 each independently represents H, Cι_galkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, hydroxy or Ci-galkoxy, or R 4 and R 5 together form a group =0; R 6 and R each independently represents H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, hydroxy or Ci-galkoxy or R and R 7 together form a group =0; R represents an optionally substituted aromatic heterocycle; R 9 represents H, C^-salkyl, C 3 _ 6 cycloalk l, C 3 _5cycloalkylmethyl, or phenyl; R 10 and R 11 each independently represent H, Cι_galkyl, C 3 _ 6 cycloalkyl or C 3 _5cycloalkylmethyl; R 12 represents NR 13 R 14 or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; R 13 and R 14 each independently represent H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, phenyl optionally substituted by one or more of Ci-gal yl, C*j__galkoxy, halo or trifluoromethyl or phenylCι_4alkyl optionally substituted in the phenyl ring by one or more of Cι_ 5 al yl, Ci-salko y, halo or trifluoromethyl; R 15 represents Ci-galkyl, C^-gcycloalkyl, C 3 __5cycloalkylmethyl, trifluoromethyl or phenyl optionally substituted by one or more substituents selected from C^-salkyl, Ci-galkoxy, halo and trifluoromethyl; Y represents a hydrocarbon chain of l, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Z represents CH2, O, S or NR 10 ; and q represents 0, 1, 2, 3, 4, 5 or 6. As used herein, the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. The alkyl, alkenyl and alkynyl groups referred to with respect to the formulae herein may represent straight or branched groups. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-propyl and n-, sec-, iso- or tert-butyl. The cycloalkyl groups referred to above may be, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Similarly, suitable cycloalkylmethyl groups include cyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl. The term "halo" as used herein includes fluoro, chloro, bromo and iodo, especially chloro and fluoro. The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I) . Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Those compounds according to the invention which contain one or more chiral centres may exist both as enantiomers and as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably m is 2. When m is 2, n is preferably 2. When m is 3 or 4, n is preferably 0. A preferred class of compounds of formula (I) is that wherein X represents a group CR R 5 C__2CR 6 R 7 , CR 4 =CHCR 6 R 7 or CR 4 R 5 CH=CR 6 . Suitably R 4 and R 5 each independently represents H, methyl, hydroxy or methoxy or R 4 and R 5 together represent =0. Suitably R 6 and R 7 each independently represents H, methyl, hydroxy or methoxy or R 6 and R 7 together represent =0. Suitable values for the group X include: Preferably X represents CR 4 R 5 CH2CR 6 R 7 such as CH 2 CH 2 C__2, CH(OH)CH 2 CH 2 or CH 2 CH 2 CH(OH) . Preferably X represents CH 2 CH 2 CH(OH) . Preferably R 1 represents substituted phenyl. When R 1 is substituted phenyl suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, t-butyl, vinyl, methoxy, phenoxy, amino and carbonylmethoxy. Preferably R 1 represents phenyl substituted by one or more groups selected from C-j__ 5 alk l such as methyl and t-butyl, halo such as chloro, fluoro and bromo, and trifluoromethyl. Preferably R 1 represents disubstituted phenyl, in particular 3,5-disubstituted phenyl, for example 3,5- disubstituted phenyl wherein the substituents are selected from Ci-galkyl, halo and trifluoromethyl. More preferably R 1 represents 3,5-bis(trifluoromethyl) phenyl. Suitable values for the group R include unsubstituted or substituted phenyl, 5-membered heteroaryl such as thienyl, 6-membered heteroaryl such as pyridyl, and benzhydryl. Preferably R represents unsubstituted or substituted phenyl. When R 2 represents substituted phenyl a preferred substituent is halo, especially fluoro. When R 8 represents a substituted aromatic heterocycle, suitable substituents in the heterocyclic ring include one or more of Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, Cι_ 6 alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR a R b , NR a COR b , CONR a R b , C0 2 R a , SR a , S0 2 R a and CH2θR a , where R a and R b are as previously defined. Particular examples of suitable substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH 2 , SCH 3 , CONH2 and cyano. Particularly preferred substituents include oxo and NH2• Suitable values for R 8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be substituted. Preferably R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. More preferably R° represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by Ci-galkyl, preferably methyl. It will be appreciated that, when the heterocyclic moiety is substituted by an oxo or thioxo substituent, different tautomeric forms are possible so that the substituent may be represented as =0 or -OH, or =S or -SH, respectively. For the avoidance of doubt, all such tautomeric forms are embraced by the present invention. When R 12 represents NR 13 R 14 , R 13 and R 14 are preferably both Ci-galkyl such as methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl or t-butyl. More preferably R 13 and R 14 will both represent methyl. When R 12 represents an aromatic or non-aromatic azacycle or azabicycle it may contain one or more additional heteroatoms selected from O, S and N or groups NR 16 , where R 16 is H, Cι_galkyl or phenylCι_ 4 alkyl, and may be unsubstituted or substituted. Suitable substituents include Ci-galkyl, Ci-galkoxy, oxo, SH, =S, halo, trifluoromethyl, NR a R b , NR a COR b , CONR a R b , C0 2 R a and CH2θR a , where R a and R are as previously defined. When R represents an aromatic azacycle or azabicycle, suitable values of R 12 include imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, benzimidazolyl, benzoxazolyl and indolyl, preferably imidazolyl, such as 2,4- imidazolyl, or pyridyl, more preferably pyridyl such as 4-, 3- or 2-pyridyl. When R 2 represents a non-aromatic azacycle or *) , azabicycle, suitable values of R- ~ - include morpholmyl, piperdinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, azanorbornanyl, azabicyclo[2.2.2]octanyl and azabicyclo[3,2.2]nonyl, preferably morpholinyl, methylpiperazinyl, quinuclidinyl (azabicyclo[2.2.2] octanyl) or azabicyclo[3.2.2]nonyl, more preferably quinuclidinyl. Suitably Y represents a hydrocarbon chain of 1 or 2 carbon atoms optionally substituted by oxo, such as CH 2 , C=0, CH(CH 3 ), CH 2 (C=0) or (C=0)CH 2 . Preferably Y represents CH2, CH(CH3) or CH2(C=0), more preferably CH2 or CH(CH 3 ) . Suitably q represents 0, 1, 2 or 3. Suitable values of R 3 include H, COR 9 such as COCH 3 , S0 R 15 such as SO2CH 3 , Cι_ 6 alkyl such as CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 and CH 2 CH 2 C(CH 3 ) 3 , c^aUcyl substituted by C0 2 R 10 such as CH 2 C0 2 CH 3 , CH 2 C0 2 H, (CH 2 ) 3 C0 2 CH 3 and (CH2) 3 C0 2 H, Ci-galkyl substituted by CONR 10 SO 2 R 15 such as CH 2 CONHS0 2 CH 3 and CH 2 CONHS0 2 C 6 H5, Cι_galkyl substituted by phenyl, Y-R 8 and CO-Z-(CH 2 ) g -R 12 . In one preferred subgroup of compounds according to the invention, R 3 represents H or Ci-salkyl, more preferably H. In a further preferred subgroup of compounds according to the invention R 3 represents Y-R 8 . A yet further preferred subgroup of compounds according to the invention is represented by compounds wherein R 3 is CO-Z-(CH 2 ) g -R 12 . A particular sub-class of compounds according to the invention is represented by compounds of formula (la) , and pharmaceutically acceptable salts and prodrugs thereof: ,20 22 ( lα) wherein R J and X are as defined for formula (I) ; R 20 and R 21 independently represent H, C ! _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a SOR a , S0 2 R a , NR a R b , NR a COR b , NR a C0 2 R b , C0 2 R a or CONR a R b , where R a and R b are as previously defined; and R 22 represents H or halo, preferably H or fluoro, Particular values of R 20 and R 21 include H, chloro, bromo, methyl, t-butyl and trifluoromethyl. Preferably R 20 and R 21 are both other than H and are located at the 3- and 5-positions of the phenyl ring. Specific compounds within the scope of the present invention include: 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)propionyl)-4- phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-l-hydroxy-3- propenyl)-4-phenylpiperidine; 4-(3-(3' ,5*-bis(trifluoromethyl)phenyl)-l-methoxy-3- propeny1)-4-phenylpiperidine; 4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-1-methoxypropyl)- 4-phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-1-hydroxypropyl)- 4-phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3-ketopropyl)-4- phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3-hydroxypropyl)■ 4-phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3-methoxypropyl)- 4-phenylpiperidine; (R)-4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-3- hydroxypropyl)-4-phenylpiperidine; (S)-4-(3-(3* ,5'-bis(trifluoromethyl)phenyl)-3- hydroxypropyl)-4-phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3-hydroxy-3- methylpropyl)-4-phenylpiperidine; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3-hydroxy-3- ethylpropyl)-4-phenylpiperidi e; 4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)propyl)-4- phenylpiperidine; 5-[4-(3-(3',5'-bis(trifluoromethyl)phenyl)propyl)-4- phenylpiperidin-1-ylmethyl]-2,4-dihydro-l,2,4-triazol-3- one; 5-[4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3- hydroxypropyl)-4-phenylpiperidin-l-ylmethyl]-2,4-dihydro- 1,2,4-triazol-3-one; and pharmaceutically acceptable salts and prodrugs thereof. For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention (such as the dibenzoyltartrate salts) or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, sulphuric acid, fumaric acid, aleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groups may also comprise quaternary ammonium salts in which the a ino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Preferred salts of the compounds according to the invention include the hydrochloride and p- toluenesulphonic acid salts. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or topical administration including administration by inhalation or insufflation. The invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) , or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which process comprises bringing a compound of formula (I) , or a salt or prodrug thereof into association with a pharmaceutically acceptable carrier. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciu phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid prefor ulation composition containing a homogeneous mixture of a compound of the present invention, or a non- toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. * Preferably the compositions are adminsitered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. For topical administration, for example as a cream, ointment or lotion, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, onothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like. The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. These may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; epilepsy; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example, diabetic or chemotherapy-induced neuropathy, and postherpetic and other neuralgias; small cell carcinomas such as small cell lung cancer; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and " asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; emesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting. The compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine. The present invention further provides a compound of formula (I) for use in therapy. According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P. The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) . For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a /3 2 -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the . bronchodilator may be administered to a patient simultaneously, sequentially or in combination. The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator. The present invention also provides a composition comprising a compound of formula (I) , a bronchodilator, and a pharmaceutically acceptable carrier. In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg of a compound of formula (I) per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. In the treatment of emesis using an injectable formulation, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician. Compounds of formula (I) wherein X represents C(=0)CH=CH or C(=0)CH=C(C 1 _ 6 alkyl) may be prepared by reaction of compounds of formula (II) with compounds of formula (III) : (II) (IN) wherein R 1 , R 2 , R 3 , and n are as defined for formula (I) and R 30 represents H or Ci-galkyl, in the presence of a base. Suitable bases of use in the reaction include alkali metal alkoxides such as, for example, sodium methoxide. The reaction is conveniently effected in a suitable organic solvent such as an alcohol, for example, methanol. Compounds of formula (I) wherein X represents CH=CHC(=0) or C(C 1 _ 6 alkyl)=CHC(=0) may be prepared by reaction of compounds of formula (IV) with compounds of formula (V) : !• (IV) (V) wherein R 1 , R 2 , R , m and n are as defined for formula (I) and R 31 represents alkoxy, in the presence of a base. Suitable bases of use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is conveniently carried out in a suitable organic solvent such as, for example, acetonitrile. Other compounds of formula (I) may be prepared from compounds of formula (I) wherein X is C(=0)CH=CH, C(=0)CH=C(C 1 _ 6 alkyl) , CH=CHC(=0) and C(C 1 _ 6 alkyl)=CHC(=0) by suitable interconversion procedures. For example, compounds of formula (I) wherein X contains a carbon-carbon double bond may be converted to compounds of formula (I) , wherein X contains no carbon- carbon double bond by reduction. Suitable procedures will be readily apparent to those skilled in the art and include catalytic hydrogenation, for example, using a nobel metal catalyst such as rhodium, platinum or, preferably, palladium, which may be supported, for example on carbon, and reaction with an alkyl tin hydride such as tributyl tin hydride. Compounds of formula (I) wherein R 4 and R 5 together represent =0 or R 6 and R 7 together represent =0 may be converted to the corresponding alcohols wherein one of R 4 and R 5 or one of R 6 and R 7 is H and the other of R 4 and R 5 or R 6 and R 7 is hydroxy by conventional reduction methods. Suitable reducing agents include hydride reducing agents such as, for example, sodium borohydride. Compounds of formula (I) wherein at least one of R 4 , R 5 , R 6 and R 7 represents Ci-galkoxy may be prepared from the corresponding alcohol of formula (I) by alkylatiσn. Suitable procedures will be readily apparent to those skilled in the art and include reaction with an alkyl halide, such as, for example, an alkyl iodide, in the presence of a base, such as an alkali metal hydride, for example sodium hydride. Compounds of formula (I) wherein R 4 and R 5 or R 6 and R 7 together form =0 may be converted to compounds of formula (I) wherein one or both of R 4 and R 5 or R 6 and R 7 represent Ci-galkyl by reaction with a Grignard reagent of formula R 4 MgHal and/or R 5 MgHal or R 6 MgHal and/or R 7 MgHal wherein Hal represents halo such as chloro, bromo or iodo. Compounds of formula (I) wherein X represents CR 4 R 5 CH=CH or CH=CHCR 6 R 7 may be prepared from the corresponding compounds of formula (I) wherein X represents CR 4 R 5 CH 2 CHOH or CH(OH)CH 2 CR 6 R 7 by treatment with Burgess Reagent ( (methoxycarbonylsulphamoyl)- triethylammoniu hydroxide, inner salt) . Interconversion processes may also be used to vary the group R . For example, compounds of formula (I) , (II) or (IV) wherein R 3 is other than H may be prepared from the corresponding compounds of formula (I) , (II) or (IV) wherein R 3 is H by conventional methods, such as reaction with a compound R 3 -Hal, where Hal represents halo, in the presence of a base. Suitable reagents and conditions will be readily apparent to those skilled in the art. Suitable bases include organic bases, such as tertiary amines, e.g. triethylamine, and inorganic bases, such as alkali metal carbonates, e.g. sodium carbonate. Compounds of formula (I) , (II) or (IV) wherein R 3 is COR may also be prepared from corresponding compounds of formula (I) , (II) or (IV) wherein R 3 is H by, for example, reaction with an appropriate acid anhydride. Compounds of formula (I) , (II) or (IV) wherein R 3 is Ci-galkyl may be prepared from corresponding compounds of formula (I) , (II) or (IV) wherein R 3 is COR by reduction using, for example, borane or a borohydride such as sodium cyanoborohydride. Suitable procedures will be readily apparent to those skilled in the art. Compounds of formula (I) , (II) or (IV) wherein R 3 is C 1 _ 6 alkyl substituted by CONR 10 R 1:L may be prepared from corresponding compounds of formula (I) , (II) or (IV) wherein R 3 is C _ 6 alkyl substituted by C0 2 by treatment with ammonia or an amine of formula NR^R 11 . Compounds of formula (II) wherein R 3 is H are commercially available or may be prepared by known procedures. Compounds of formulae (III) and (V) are commercially available or may be prepared from commercially available compounds by procedures well known in the art. Compounds of formula (IV) may be prepared from the corresponding compounds of formula (VI) AA (VI ) wherein R 2 , R 3 , m and n are as previsouly defined, by reduction. A suitable reducing agent for use in the reaction is diisobutyl aluminium hydride. Compounds of formula (VI) are commerically available or may be prepared by known procedures. Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. The novel compounds which contain one or more chiral centres may be prepared in racemic form, or individual enantio ers may be prepared either by enantiospecific synthesis or by resolution. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The exemplified compounds of the invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC 50 at the NK^ receptor of less than 300nM. The compounds of this invention may be formulated as specifically illustrated at pages 35 to 36 of International Patent Specification No. 93/01165. The following Examples illustrate the preparation of compounds according to the invention. EXAMPLE 1 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)propionyl ,-4- phenylpiperidine Hydrochloride (a) 4-Acetyl-N- t butoxycarbonyl-4-phenylpiperidine 4-Acetyl-4-phenylpiperidine hydrochloride was dissolved in water, the solution was made basic by addition of potassium carbonate, and the mixture was extracted with ethyl acetate. The extracts were dried (Na 2 SO 4 ) and concentrated to give 4- acetyl-4-phenylpiperidine. To a solution of this compound (2.2g) in dichloromethane (50ml) was added di- e butyl dicarbonate (2.8g). After 15 minutes the solution was washed with water, dried, concentrated and the residue crystallised from petroleum ether to give the title compound, mp 91-92°C. (b) N- t Butoxycarbonyl-4-(3'.5'- bis(trifluoromethyl)cinnamoyl)-4-phenylpiperidine The compound of part (a) (9.3g) in methanol (250ml) was heated under reflux with 3,5-bis(trifluoromethyl)benzaldehyde (12.5g) in the presence of sodium methoxide (0.5g) for 3 hours. The solvent was removed in υacuo and the residue partitioned between water and ethyl acetate. The ethyl acetate solution was separated, dried and concentrated to give a residue which was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:9) to give the title compound. Η NMR (250MHz, CDC1 3 ) 5 1.45 (9H, s), 1.90-2.18 (2H, m), 2.40- 2.50 (2H, m), 3.01-3.30 (2H, m), 3.70-4.10 (2H, m), 6.72 (IH, d, J = 16Hz), 7.26-7.44 (5H, m), 7.66 (IH, d, J = 16Hz), 7.79 (2H, s), 7.82 (IH, s). (c) 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)propionyl)-4- phenylpiperidine Hydrochloride The compound of part (b) (7.2g) in toluene (50ml) was purged with nitrogen gas and tributyltin hydride (4.8g) was added. The reaction was heated to reflux for 16 hours then cooled and concentrated in υacuo. The product was purified by chromatography on silica eluting with ethyl acetate/petroleum ether (3:7), then dissolved in ethereal hydrogen chloride for 16 hours. The solvent was then evaporated to yield the title compound, mp 164-165°C; found: C, 56.82; H, 4.75; N, 2.95. C 22 H 21 F 6 NO.HCl requires C, 56.72; H, 4.76; N, 3.01. EXAMPLE 2 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-l-hvdroxy-3-propenyl.- 4-phenylpiperidine Hydrochloride The compound of Example 1(b) (lg) in methanol (20ml) was stirred with sodium borohydride (0.2g) for 1 hour. The solution was poured into water and extracted with ethyl acetate which was then dried (Na 2 S0 4 ) and concentrated in υacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (3:7) then dissolved in ethereal hydrogen chloride. The solid which crystallised from solution was filtered to give the title compound, mp 174-175°C; found: C, 53.98; H, 4.76; N, 2.94. C 22 H 21 F 6 NO.HC1.1.25H 2 O requires C, 54.10; H, 5.06; N, 2.89. EXAMPLE 3 4-(3-(3'.5'-Bis(trifluoromethyl .phenyl)-l-methoxy-3- propenyl.-4-phenylpiperidme Hydrochloride The compound of Example 1(b) was reduced with sodium borohydride as described in Example 2. After purification on silica gel the product was treated with sodium hydride and methyl iodide in dimethylformamide for one hour. The solution was poured onto water and extracted with ethyl acetate which was then dried (Na 2 S0 4 ) and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (15:85), then dissolved in ethereal hydrogen chloride. The solid which crystallised from solution was filtered and dried to give the title compound, mp 282°C; found: C, 57.06; H, 4.93; N, 2.88. C 23 H 23 F 6 NO.HC1.0.25H 2 O requires C, 57.03; H, 5.10; N, 2.89. EXAMPLE 4 4-(3-(3'.5'-Bis( trifluoromethyl )phenyl)-l-hvdroxypropyl)-4- phenylpiperidine Hydrochloride The compound of Example Kb) was treated with tributyltin hydride as described in Example 1(c). After purification on silica gel the product was reduced using sodium borohydride and treated with ethereal hydrogen chloride, as described in Example 2, to give the title compound, mp 90-91°C; found: C, 54.81; H, 5.04; N, 2.86. C 22 H 23 F 6 NO.HC1.0.75H 2 O requires C, 54.89; H, 5.34; N, 2.91. EXAMPLE 5 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-l-methoxypropyl)-4- phenylpiperidine Hydrochloride The compound of Example Kb) was treated with tributyltin hydride then sodium borohydride as described in Example 4. After purification on silica gel the product was reacted with sodium hydride and methyl iodide by the method of Example 3. The product was purified on silica gel and dissolved in ethereal hydrogen chloride for 16 hours. The solvent was removed in υacuo to give the title compound, mp 65-67°C; found: C, 57.58; H, 5.36; N, 2.87. C 23 H 25 F 6 NO.HCl requires C, 57.32; H, 5.44; N, 2.91. EXAMPLE 6 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3-ketopropylV4- phenylpiperidine Hydrochloride (a) Dimethyl 2-(3.5-bis(trifluoromethyl)phenyl-2-keto- ethylphosphonate Dimethyl methylphosphonate (50. lg) in tetrahydrofuran (500ml) was treated with butyl lithium (165ml of a 2.5M solution in hexane) at -78°C under an atmosphere of nitrogen. After 1 hour, methyl 3,5-bis(trifluoromethyl)benzoate (18.7g) in tetrahydrofuran (50ml) was added slowly and stirred for 0.5 hours. The reaction was quenched with 5N hydrochloric acid (500ml) and the tetrahydrofuran evaporated in υacuo. The resulting mixture was extracted with ethyl acetate which was then dried and concentrated under reduced pressure. The residue was distilled under vacuum at 1mm Hg to give the title compound, bp 160-162°C. (b) N- nutoxycarbonyl-4-phenyl-4-cvano piperidine Di-T_>utyldicarbonate (20g) was added to a stirred solution of 4-phenyl-4-cyano piperidine hydrochloride (20g) and EtoN (9.5g) in dry dichloromethane (100ml). The resulting solution was stirred for 18 hours at room temperature. The reaction mixture was washed with water (100ml) and the organic layer separated and dried over MgSO . Filtration and removal of solvent under reduced pressure afforded a white solid. Recrystallisation from hexane gave the title compound as white needles, mp = 64°C. 1H NMR (360MHz, CDClg) δ 1.46 (9H, s), 1.90 (2H, m), 2.04 (2H, m), 3.20 (2H, m), 4.26 (2H, m), 7.26-7.49 (5H, m); MS (CI + ) 287 (M + H + ). (c) N- utoxycarbonyl-4-phenylpiperidine- 4-carboxaldehvde A solution of N- Εutoxycarbonyl-4-phenyl-4-cyano piperidine (5.0g) in dry toluene (100ml) at -78°C was treated with a solution of DIBALH (27.7ml x l.Omol) in toluene. The reaction was maintained at -78°C for two hours, at which time it was quenched by slow addition of a saturated solution of NH Cl (20ml), and allowed to warm to room temperature. The reaction mixture was poured into water (100ml) and extracted into ethyl acetate. The organic layers were separated, dried over MgSO , filtered and solvent removed to give a yellow oil. Chromatography on silica gel (20% EtOAc in hexane) afforded the product as a clear oil (2.1g). 1H NMR (360MHz, CDCy ~ 1.45 (9H, s), 1.95 (2H, m), 2.07 (2H, m), 3.12 (2H, m), 3.85 (2H, m), 7.26-7.40 (5H, m), 9.40 (IH, s); MS (CI + ) 290 (M + H + ). (d) 4-(3-(3'.5'-Bis(trifluoromethyl .phenyl)-3-keto-2- propenyl)-4-phenyl-N- t butoxycarbonylpiperidine The compounds of Examples 6(a) (4.6g) and 6(c) (5.8g) were stirred in dimethylformamide (100ml) in the presence of sodium hydride (0.8g of a 60% dispersion in oil) for 1 hour. •Propyl alcohol was added then the solvents were removed in υacuo. The residue was purified on silica gel eluting with ethyl acetate-petroleum ether (1:9) to give the title compound. 1 H NMR (360MHz, CDC1 3 ) δ 1.46 (9H, s), 1.86-2.10 (2H, m), 2.30- 2.46 (2H, m), 3.04-3.20 (2H, m), 3.84-3.98 (2H, m), 7.21-7.48 (5H, m), 7.99 (IH, s), 8.10 (2H, s). (e) 4-(3-(3'.5'-Bis(trifluoromethyl,phenyl)-3-ketopropyl)-4- phenyl-N- t butoxycarbonylpiperidine The compound of Example 6(c) (1.4g) was shaken in ethanol (25ml) under an atmosphere of hydrogen over 10% Pd-C (lg) at 50 psi for 16 hours. The mixture was filtered and evaporated to give the title compound. Η NMR (360_v_Hz, CDC1 3 ) δ 1.45 (9H, s), 2.04-2.14 (2H, m), 2.25-2.35 (2H, m), 3.42- 3.49 (2H, m), 3.55-3.62 (2H, m), 6.61 (IH, d, J = 16Hz), 7.15 (IH, d, J = 16Hz), 7.26-7.46 (5H, m), 8.03 (IH, s), 8.22 (2H, s). (f) 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3-ketopropyl)-4- phenylpiperidine Hydrochloride The compound of Example 6(d) was treated with ethereal hydrogen chloride for 16 hours then concentrated in υacuo to give the title compound as a white solid, mp 54-55°C; found: C, 55.48; H, 4.74; N, 2.78. C 22 H 21 F 6 NO.HC1.0.5H 2 O requires C, 55.64; H, 4.88; N, 2.95. EXAMPLE 7 4-(3-(3'.5'-Bis(trifluoromethyl,phenyl .-3-hvdroxypropyl)-4- phenylpiperidine Hydrochloride (a) 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3- hvdroxypropyl)-N- t butoxycarbonyl-4-p_ιenylpiperidine The compound of Example 6(e) (1.5g) in methanol (20ml) was treated with sodium borohydride (0.3g) for 1 hour. The reaction mixture was poured onto water and extracted with ethyl acetate which was then dried (Na 2 SO 4 ) and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:4) to give the title compound. -H NMR (360MHz, CDC1 3 ) δl.43 (9H, s), 1.47-1.73 (2H, m), 2.04-2.17 (2H, m), 3.02-3.14 (2H, m), 3.58-3.66 (2H, m), 4.56-4.58 (IH, m), 7.19-7.34 (5H, m), 7.61 (2H, s), 7.74 (IH, s). (b) 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3-hvdroxypropyl)- 4-phenylpiperidine Hydrochloride The compound of part (a) was dissolved in ethereal hydrogen chloride for 16 hours. The solvent was evaporated in υacuo to give the title compound, mp 95-96°C. EXAMPLE 8 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3-methoxypropyl)-4- phenylpiperidine Hydrochloride The compound of Example 7(a) (0.5g) in dimethylformamide (20ml) was stirred with methyl iodide (0.29g) and sodium hydride (0.06g of a 60% suspension in oil) for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried (Na 2 SO 4 ) and concentrated. The residue was purified by chromatography on silica gel then dissolved in ethereal hydrogen chloride for 16 hours. The solvent was removed under reduced pressure to give the title compound as a white solid, mp 186-187°C; found: C, 55.27; H, 5.47; N, 2.82. C 23 H 25 F 6 NO.HCl.H 2 O requires C, 55.26; H, 5.65; N, 2.80. EXAMPLE 9 R- and S-4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3- hvdroxypropyl)-4-phenylpiperidine Hydrochloride The compound of Example 7(a) (lOOmg) was dissolved in dichloromethane (10ml) and stirred for 1.5 hours with triethylamine (0.03ml), 4-(dimethylamino)pyridine (5mg) and α- methoxyl-α-(trifluoromethyl)phenylacetyl chloride (0.04ml). The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate solution was concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate- petroleum ether (7:93) to give two products, diastereomer A and diastereomer B. These two diastereomers were individually heated under reflux with sodium hydroxide in methanol for 1 hour. In each case the solvent was removed in υacuo and the residue purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:4) to give R- and S-4-(3-(3',5'- bis(trifluoromethyl)phenyl)-3-hydroxypropyl)-N- t butoxycarbonyl- 4-phenylpiperidine. These two enantiomers were individually treated with ethereal hydrogen chloride as described in Example 7(b) to give the title compounds. Enantiomer A, mp 81-82°C, α D (c=1.03, MeOH) = + 9.32°; Enantiomer B, mp 83-84°C, α D (c=0.96, MeOH) = -8.85°. EXAMPLE 10 4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)-3-hvdroxy-3- methylpropyl)-4-phenylpiperidine Hydrochloride The compound of Example 6(c) (0.41g) in diethyl ether (10ml) was treated with methylmagnesium bromide (0.8ml of a 3M solution in tetrahydrofuran) for 5 minutes after which time water was added and extracted with diethyl ether. The ethereal extracts were dried (Na 2 SO 4 ) and concentrated to give a residue which was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3). The resulting oil was treated with ethereal hydrogen chloride for 4 hours then concentrated to give the title compound as a white solid, mp 213- 215°C; found: C, 56.26; H, 5.42; N, 2.93. C 23 H 25 F 6 NO.HCl. 0.5H 2 O requires C, 56.27; H, 5.54; N, 2.85. EXAMPLE 11 4-(3-(3'.5'-Bis(trifluoromethyl)phenylV3-hvdroxy-3- ethylpropyl.-4-phenylpiperidine Hydrochloride Prepared by the method of Example 10 using ethylmagnesium bromide. Mp 105°C; found: C, 57.13; H, 5.83; N, 2.76. C 24 H 27 F 6 NO.HC1.0.5H 2 O requires C, 57.09; H, 5.79; N, 2.77. EXAMPLE 12 4-(3-(3'.5'-Bis(trifluoromethyl.phenyl)propyl)-4- phenylpiperidine Hydrochloride The compound of Example 7(a) (0.7g) in dichloromethane (50ml) with 4-(dimethylamino)pyridine (0.32g) was cooled to 0°C. Phenyl chlorothiocarbamate (0.43g) was added and the solution allowed to warm to 20°C and stirred for 16 hours. The mixture was diluted with ethyl acetate and washed successively with a solution of citric acid in water, then water, sodium bicarbonate solution, and water. The solution was dried (Na 2 SO 4 ), concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:9). The resulting product was dissolved in toluene (25ml) which was purged with nitrogen gas. Alpha, alpha'-azoisobutyronitrile (0.49g) and tributyltin hydride (0.58g) were added and the solution was heated under reflux for 5 hours then cooled and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate- petroleum ether (1:9) then treated with ethereal hydrogen chloride for 16 hours. The solvent was removed in υacuo and the residue crystallised from ethyl acetate to give the title compound. Η NMR (360MHz, D 6 -DMSO) δ 1.22-1.32 (2H, m), 1.54-1.64 (2H, ), 1.83-1.94 (2H, m), 2.26-2.34 (2H, m), 2.62 (2H, t, J = 7.5Hz), 2.72 (2H, t, J = lOHz), 3.08-3.18 (2H, m), 7.21-7.37 (5H, m), 7.76 (2H, s), 7.86 (IH, s), 8.74 (IH, s); MS (CI + ) 416 (M+H EXAMPLE 13 5-r4-(3-(3'.5'-Bis(trifluoromethyl)phenyl)propyl)-4- phenylpiperidin-l-ylmethyl " l-2.4-dihvdro-1.2.4-triazol-3-one N- t -Butoxychloromethyl imidrazone (104.4mg) was added to a stirred suspension of the compound of Example 12 (310mg) (l.Og) in dry dimethylformamide (15ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with water (50ml) and extracted into ethyl acetate (50ml). The organic extract was washed with water (4 x 20ml), brine (50ml) and dried over MgSO 4 . Filtration and removal of solvent under reduced pressure afforded a yellow crystalline solid (290mg) which was re-dissolved in dry toluene (20ml) and warmed to reflux in the presence of a catalytic amount of potassium t-butoxide. After 4 hours the reaction was cooled to room temperature and the solvent removed under reduced pressure. Recrystallisation from diethyl ether-hexane afforded the title compound as a white powder, mp 104-105°C. EXAMPLE 14 5- .4-(3-(3 ' .5 '-Bi s.trifluorometh yl )phen yl )-3-hydroxyprop yl ) -4- phenylpiperidin-l-ylmethyll-2.4-dihvdro-1.2.4-triazol-3-one Prepared from the compound of Example 7 using the method of Example 7 using the method of Example 14. Mp 110°C; found: C, 55.30; H, 5.05; N, 10.09. C 25 H 26 F 6 N 4 O 2 .0.75H 2 O requires C, 55.40; H, 5.11; N, 10.33.

Claims: CLAIMS 1. A compound of formula (I) , or a pharmaceutically acceptable salt or prodrug thereof; R 3 ( I) wherein X represents a propylene or propenylene chain opt_:iioonnaallllyy substituted by one or more of R , R , R° and R' m is 2, 3 or 4; n is 0, 1 or 2 when m is 2 or 3, and n is 0 or 1 when m is 4; R 1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C 2 _ 6 alkenyl, C 2 _galkynyl, C 3 _6cycloalkyl, C 3 _ 5 cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b each independently represent H, Ci-galkyl, phenyl or trifluoromethyl; R 2 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C _galkenyl, C _galkynyl, C 3 _gcycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a C0R b , -NR a C0 2 R b , -C0 2 R a or -C0NR a R b , where R a and R b are as previously defined; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each heteroaryl and each phenyl moiety of benzyl and benzhydryl may be substituted by Ci-galkyl, Ci-galkoxy, halo or trifluoromethyl; R 3 represents H, COR 9 , C0 2 R 10 , COCONR 10 R 1: 5-, COC0 2 R 10 , S0 2 R 15 , CONR 10 SO 2 R 15 , Cx-galk l optionally substituted by a group selected from (C0 R 10 , CONR 10 R 11 , hydroxy, cyano, COR 9 , NR 10 R ι:L , C(NOH)NR 10 R 1:L , CONHphenyl(C 1 _ 4 alkyl) , COC0 2 R 10 , COCONR 10 R 1:L , S0 2 R 15 , CONR 10 SO 2 R 15 and phenyl optionally substituted by one or more substituents selected from Ci-gal yl, Ci-galkoxy, halo and trifluoromethyl), Y-R 8 or CO-Z-(CH 2 ) q -R 12 ; R 4 and R 5 each independently represents H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 -5cycloalkylmethyl, hydroxy or Cι_- 6 l o y, or R 4 and R 5 together form a group =0; R 6 and R each independently represents H, Cι_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, hydroxy or Cι_ 6 alkoxy or R and R 7 together form a group =0; R° represents an optionally substituted aromatic heterocycle; R 9 represents H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, or phenyl; R 10 and R 11 each independently represent H, Cι_galkyl, C 3 _ 6 cycloalkyl or C 3 _ 5 cycloalkylmethyl; R 12 represents NR 13 R 14 or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; R 13 and R 14 each independently represent H, Cι_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, phenyl optionally substituted by one or more of Ci-salkyl, Ci-salkoxy, halo or trifluoromethyl or phenylCι_4alkyl optionally substituted in the phenyl ring by one or more of C^-galkyl, C^-galkoxy, halo or trifluoromethyl; R 15 represents Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, trifluoromethyl or phenyl optionally substituted by one or more substituents selected from Ci-galkyl, Ci-galkoxy, halo and trifluoromethyl; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Z represents CH 2 , 0, S or NR 10 ; and q represents 0, 1, 2, 3, 4, 5 or 6. 2. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof: —X \ / R 3 ( I ) wherein X represents a group CR 4 R 5 CH 2 CR 6 R 7 , CR 4 =CHCR 6 R 7 or CR 4 R 5 CH=CR 6 ; m is 2, 3 or 4; n is 0, 1 or 2 when is 2 or 3, and n is 0 or 1 when m is 4; R represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C 2 _ 5 alkenyl, C 2 _galkynyl, C 3 _ 6 cycloal yl, C 3 _ 5 cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -0R a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b each independently represent H, Ci-galkyl, phenyl or trifluoromethyl; R 2 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C 2 _galkenyl, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b are as previously defined; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each heteroaryl and each phenyl moiety of benzyl and benzhydryl may be substituted by C^-galkyl, Ci-βalkoxy, halo or trifluoromethyl; R 3 represents H, COR 9 , C0 2 R 10 , COCONR 10 R 1:L , COC0 2 R 10 , S0 2 R 15 , CONR 10 SO 2 R 15 , Ci-ealkyl optionally substituted by a group selected from (C0 R 10 , CONR 10 R 11 , hydroxy, cyano, COR 9 , NR 10 R 1:L , C(NOH)NR 10 R 1:L , CONHphenyl(C 1 _ 4 alkyl) , COC0 2 R 10 , COCONR 10 R i:L , S0 2 R 15 , CONR 10 SO 2 R 15 and phenyl optionally substituted by one or more substituents selected from Ci-galkyl, C^-galkoxy, halo and trifluoromethyl), Y-R 8 or CO-Z-(CH 2 ) q -R 12 ; R 4 and R each independently represents H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, hydroxy or Ci-galkoxy, or R 4 and R 5 together form a group =0; R 6 and R 7 each independently represents H, Cι_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, hydroxy or Ci-galkoxy or R 6 and R 7 together form a group =0; R 8 represents an optionally substituted aromatic heterocycle; R R 99 rreepprreesseernts H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, or phenyl; R R 1100 aanndd RR 1111 eeaacchh iinnddeeppendently represent H, Cι_galkyl, C 3 _ 6 cycloalkyl or C 3 _5cycloalkylmethyl; R 12 represents NR 13 R 14 or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; R 13 and R 14 each independently represent H, Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _5cycloalkylmethyl, phenyl optionally substituted by one or more of Ci-gal yl, Ci-galkoxy, halo or trifluoromethyl or phenylCι_ 4 alkyl optionally substituted in the phenyl ring by one or more of Ci-gal yl, Ci-galkoxy, halo or trifluoromethyl; R 15 represents Ci-galkyl, C 3 _ 6 cycloalkyl, C 3 _ 5 cycloalkylmethyl, trifluoromethyl or phenyl optionally substituted by one or more substituents selected from Ci-galkyl, C^-galkoxy, halo and trifluoromethyl; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Z represents CH , O, S or NR 10 ; and q represents 0, 1, 2, 3, 4, 5 or 6. 3. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof: (I) wherein X represents a group CR 4 R 5 CH 2 CR 6 R 7 , CR 4 =CHCR 6 R 7 or CR 4 R 5 CH=CR 6 ; m is 2, 3 or 4; n is 0, 1 or 2 when is 2 or 3, and n is 0 or 1 when m is 4; R 1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C 2 _ 6 alkenyl, C 2 _galkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b each independently represent H, Ci-g lkyl, phenyl or trifluoromethyl; R 2 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C _ 6 alkenyl, C2- 6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , -SR a , -SOR a , -S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b , where R a and R b are as previously defined; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each heteroaryl and each phenyl moiety of benzyl and benzhydryl may be substituted by Ci-galkyl, Ci-galkoxy, halo or trifluoromethyl; R 3 represents H, COR 9 , C0 2 R 10 , COCONR 10 R 1:L , COC0 2 R 10 , S0 2 R 15 , CONR 10 SO 2 R 15 , Cx-g lkyl optionally substituted by a group selected from (C0 2 R 1 , CONR 10 R 11 , hydroxy, cyano, COR 9 , NR 10 R 1:L , C(NOH)NR 10 R 1:L , CONHphenyl(Cχ- 4 alkyl) , COC0 2 R 10 , COCONR 10 R 1:L , S0 2 R 15 , CONR 10 SO 2 R 15 and phenyl optionally substituted by one or more substituents selected from Ci-galkyl, Cι_galkoxy, halo and trifluoromethyl), Y-R 8 or CO-Z-(CH 2 ) g -R 12 ; R 4 and R each independently represents H, Cι_galkyl, hydroxy or Ci-galkoxy, or R 4 and R together form a group =0; R 6 and R 7 each independently represents H, Ci-galkyl, hydroxy or Ci-galkoxy or R 6 and R 7 together form a group =0; R R 88 rreepp:resents an optionally substituted aromatic heterocycle; R R 99 rreepprreesseenn-ts H, Ci-galkyl or phenyl; R 10 and R each independently represent H or Ci-galkyl; R 12 represents NR 13 R 14 or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; R 13 and R 14 each independently represent H, Ci-galkyl, phenyl optionally substituted by one or more of Ci-galkyl, Ci-galkoxy, halo or trifluoromethyl or phenylCι_ 4 alkyl optionally substituted in the phenyl ring by one or more of C^-galkyl, Ci-galkoxy, halo or trifluoromethyl; R 15 represents Cι_galkyl, trifluoromethyl or phenyl optionally substituted by one or more substituents selected from C^-galkyl, C^-galkoxy, halo and trifluoromethyl; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Z represents CH 2 , O, S or NR 10 ; and q represents 0, 1, 2, 3, 4, 5 or 6. 4. A compound as claimed in Claim 1 of formula (la) , or a pharmaceutically acceptable salt or prodrug thereof: (lα) wherein R 3 and X are as claimed in Claim 1; R 20 and R 21 independently represent H, Ci-galkyl, C 2 _galkenyl, C 2 _galkynyl, C 3 _gcycloalkyl, C 3 _5cycloalkylmethyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a SOR a , S0 2 R a , NR a R b , NR a C0R b , NR a C0 2 R b , C0 2 R a or CONR a R b , where R a and R b are as previously defined; and R 22 represents H or halo. 5. A compound as claimed in any one of Claims 1 to 3 wherein m is 2 and n is 2. 6. A compound as claimed in any one of Claims 1 to 5 wherein R 4 , R 5 , R 6 and R 7 each independently represent H, methyl, hydroxy or methoxy or R 4 and R 5 , or Rfi° and R7, together represent =0. 7. A compound as claimed in any one of Claims 1 to 6 wherein X represents a group selected from: 8. A compound as claimed in Claim 7 wherein X represents CH 2 CH 2 CH(OH) . 9. A compound as claimed in any one of Claims 1 to 8 wherein R 1 represents phenyl substituted by 1, 2 or 3 groups selected from nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, t-butyl, vinyl, methoxy, phenoxy, amino and carbonylmethoxy. 10. A compound as claimed in Claim 9 wherein R 1 represents 3,5-disubstituted phenyl wherein the substituents are selected from Cι_galkyl, halo and trifluoromethyl. 11. A compound as claimed in Claim 10 wherein R 1 represents 3,5-bis(trifluoromethyl)phenyl. 12. A compound as claimed in any one of Claims 1 to 11 wherein R 2 represents unsubstituted or substituted phenyl. 13. A compound as claimed in any one of Claims 1 to 12 wherein R 3 is H. 14. A compound as claimed in any one of Claims 1 to 12 wherein R 3 is Y-R 8 wherein Y is as defined in Claim 1 and R 8 is selected from thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be substituted by one or more of Cι_galkyl, C 3 _gcycloalkyl, C 3 _ 5 cycloalkylmethyl, Cι_galkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR a R b , NR a COR b , CONR a R b , C0 2 R a , SR a , S0 2 R a and CH 2 OR a , where R a and R b are as defined in Claim 1. 15. A compound as claimed in any one of Claims 1 to 12 or 14 wherein Y represents a hydrocarbon chain of 1 or 2 carbon atoms optionally substituted by oxo. 16. A compound selected from 4-(3-(3 • ,5'-bis(trifluoromethyl)phenyl)propionyl)-4- phenylpiperidine; 4-(3-(3 » ,5•-bis(trifluoromethyl)phenyl)-l-hydroxy-3- propenyl)-4-phenylpiperidine; 4-(3-(3• ,5*-bis(trifluoromethyl)phenyl)-l-methoxy-3- propenyl)-4-phenylpiperidine; 4-(3-(3 » ,5'-bis(trifluoromethyl)phenyl)-l-methoxypropyl)- 4-phenylpiperidine; 4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-1-hydroxypropyl)- 4-phenylpiperidine; 4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-3-ketopropyl)-4- phenylpiperidine; 4-(3-(3• ,5*-bis(trifluoromethyl)phenyl)-3-hydroxypropyl)- 4-phenylpiperidine; 4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-3-methoxypropyl)- 4-phenylpiperidine; (R)-4-(3-(3• ,5'-bis(trifluoromethyl)phenyl)-3- hydroxypropyl)-4-phenylpiperidine; (S)-4-(3-(3' ,5'-bis(trifluoromethyl)phenyl)-3- hydroxypropyl)-4-phenylpiperidine; 4-(3-(3 ' ,5'-bis(trifluoromethyl)phenyl)-3-hydroxy-3- methylpropyl)-4-phenylpiperidine; 4-(3-(3' ,5*-bis(trifluoromethyl)phenyl)-3-hydroxy-3- ethylpropyl)-4-phenylpiperidine; 4-(3-(3 * ,5'-bis(trifluoromethyl)phenyl)propyl)-4- phenylpiperidine; 5-[4-(3-(3*,5'-bis(trifluoromethyl)phenyl)propyl)-4- phenylpiperidin-1-ylmethyl]-2,4-dihydro-l,2,4-triazol-3- one; 5-[4-(3-(3• ,5'-bis(trifluoromethyl) henyl)-3- hydroxypropy1)-4-phenylpiperidin-l-ylmethyl]-2,4-dihydro- 1,2,4-triazol-3-one; or a pharmaceutically acceptable salt or prodrug thereof. 17. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or prodrug thereof in association with a pharmaceutically acceptable carrier. 18. A compound of formula (I) as claimed in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or prodrug thereof for use in therapy. 19. The use of a compound of formula (I) as claimed in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P. 20. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound as claimed in Claim 1, or a pharmaceutically acceptable salt of prodrug thereof, or a composition comprising a compound as claimed in Claim 1, or a pharmaceutically acceptable salt or prodrug thereof, in association with a pharmaceutically acceptable carrier. 21. A process for the preparation of a compound as claimed in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or prodrug thereof which comprises: (A) reacting a compound of formula (II) with a compound of formula (III) wherein R 1 , R 2 , R 3 , and n are as defined in Claim 1 and R ° represents H or C^-galkyl, in the presence of a base; or (B) reacting a compound of formula (IV) with a compound of formula (V) (V) wherein R 1 , R 2 , R 3 , m and n are as defined in Claim 1 and R 31 represents Cι_ 6 alkoxy, in the presence of a base; in each case followed, if desired, by interconversion into another compound of formula (I) or (la) ; and/or followed, if necessary, by deprotection.

Inventors: MACLEOD ANGUS MURRAY, MERCHANT KEVIN JOHN, STEVENSON GRAEME IRVINE, MACLEOD, ANGUS, MURRAY, MERCHANT, KEVIN, JOHN, STEVENSON, GRAEME, IRVINE
Applicants: MACLEOD ANGUS MURRAY, MERCHANT KEVIN JOHN, MERCK SHARP & DOHME, STEVENSON GRAEME IRVINE, MACLEOD, ANGUS, MURRAY, MERCHANT, KEVIN, JOHN, MERCK SHARP & DOHME LIMITED, STEVENSON, GRAEME, IRVINE
Application year: 1994
Main classification: C07D211
IPC codes: A61K31, A61P1, A61P25, A61P29, A61P43, C07D211, C07D401